Inhibition of pulmonary artery smooth muscle cells via the delivery of curcuminoid WZ35 by Cu-based metal organic frameworks.

Hypoxic pulmonary hypertension (HPH) is a life-threatening disease that occurs due to a lack of oxygen in the lungs, leading to an increase in pulmonary vascular resistance, right ventricular failure, and ultimately death. HPH is a multifactorial disorder that involves multiple molecular pathways, making it a challenge for clinicians to identify effective therapies. Pulmonary artery smooth muscle cells (PASMCs) play a crucial role in HPH pathogenesis by proliferating, resisting apoptosis, and promoting vascular remodelling. Curcumin, a natural polyphenolic compound, has shown potential as a therapeutic agent for HPH by reducing pulmonary vascular resistance, inhibiting vascular remodelling, and promoting apoptosis of PASMCs. Regulation of PASMCs could significantly inhibits HPH. However, curcumin has the disadvantages of poor solubility and low bioavailability, and its derivative WZ35 has better biosafety. Here, Cu-based metal organic frameworks (MOFCu ) was fabricated to encapsulate the curcumin analogue WZ35 (MOFCu @WZ35) for the inhibition of PASMCs proliferation. The authors found that the MOFCu @WZ35 could promote the death of PASMCs. Furthermore, the authors believed that this drug delivery system will effectively alleviate the HPH.

Optimizing pH-sensitive and time-dependent polymer formula of colonic pH-responsive pellets to achieve precise drug release.

Time-sensitive and pH-dependent polymers are generally employed to prepare colon-site delivery system, and their coating thickness and order are very important in controlling the drug release. The traditional colon-site delivery systems consist of time-dependent polymers as inner layer and pH-sensitive polymers as outer layer. However, they suffer from low drug-loading rate and immature drug release. In this study, total alkaloids of sophora alopecuroides(TASA)-loaded pellets were prepared by extrusion-spheronization method and coated with Eudragit RS30D and Eudragit S100. Pellets using Eudragit RS30D as inner layer and Eudragit S100 as outer layer were named as ERS-ES100 TCO, while pellets with Eudragit S100 as inner layer and Eudragit RS30D as outer layer were ES100-ERS NCO. Both types of formulations with varying coating ratios and orders of Eudragit S100 and Eudragit RS30D were designed and prepared. The following in vitro drug release and SEM studies indicated that ERS-ES100 TCO(F2) with 12.8% Eudragit RS30D as inner layer and 21% Eudragit S100 as outer layer released up to 42% drug in 5 h. Interestingly, ES100-ERS NCO (F4) coated with 12.8% Eudragit S100 and 14.8% Eudragit RS30D showed optimal drug release in colon. In conclusion, ES100-ERS NCO colonic delivery system achieved reduced coating thickness and improved colonic targeting compared with traditional delivery system (ERS-ES100 TCO). In addition, the similarity factors (f2 ) value of sophoridine and matrine for investigated formulation were within 50-100 and > 80, demonstrating that sophoridine and matrine in all formulations achieved a synchronous release.

Chromium supplementation for adjuvant treatment of type 2 diabetes mellitus: Results from a pooled analysis.

SCOPE: We conducted a pooled analysis of randomized controlled trials to evaluate the effects of chromium supplementation on clinically relevant metabolic biomarkers in type 2 diabetes mellitus (T2DM) patients. METHODS AND RESULTS: Electronic searches were conducted and the bibliographies of located articles were searched, and 28 studies were suitable for statistical pooling. Endpoints were calculated as weighted mean differences (WMDs) with 95% confidence intervals (CIs) by using fixed-effects or random-effects models. Statistical heterogeneity, publication bias, subgroup analyses, sensitivity analysis and meta-regression assessments were also assessed. Chromium reduced levels of fasting plasma glucose (WMD, -0.99 mmol/L; 95% CI, -1.72 to -0.25; p = 0.008), hemoglobin A1c (WMD, -0.54 %; 95% CI, -0.82 to -0.25; p = 0.0002), triglycerides (WMD, -11.71 mg/dL; 95% CI, -18.38 to -5.04; p = 0.0006). Chromium also increased levels of high-density lipoprotein cholesterol (WMD, 1.73 mg/dL; 95% CI, 0.50 to 2.96; p = 0.006). These results were robust in sensitivity analysis and were not dependent on the chromium dose and duration of supplementation. Subgroup analyses indicated that these notably favorable effects were presented in T2DM subjects ingesting chromium chloride and chromium picolinate formulations. CONCLUSION: Our pooled analysis suggested that chromium supplementation might be a candidate as an adjunct to pharmacological management in patients with T2DM.

Clinicopathological Significance of MTA 1 Expression in Patients with Non-Small Cell Lung Cancer: A Meta-Analysis

Background: Metastasis associated gene 1(MTA1) is one of the most deregulated molecules in human cancer and leads to cancer progression and metastasis. We performed a meta-analysis to determine the correlations between MTA1 expression and the clinicopathological characteristics of non-small cell lung cancer (NSCLC). Methods: We searched PubMed, Springer, Science Direct, Google Scholar and China National Knowledge Infrastructure (CNKI) for relevant articles. For statistical analyses, we used R3.1.1 software. The fixed or random effects model was employed based on the results of the statistical test for homogeneity. Results: Seven studies involving 660 NSCLC patients were included. The proportion of MTA1 overexpression with 95% confidence interval (95% CI) was 0.53(95%CI: 0.43-0.62) in NSCLC patients; 0.47(95%CI: 0.40-0.55) in age <60 years and 0.52(95%CI: 0.34-0.70) in age ≥60 years; 0.5(95%CI: 0.41- 0.62) in males and 0.51(95%CI: 0.39-0.62) in females; 0.59(95%CI: 0.48-0.69) in squamous cell carcinoma (SC) and 0.57(95%CI: 0.46-0.67) in adenocarcinoma (AC); 0.39(95%CI: 0.23-0.56) in well-differentiated tumors, 0.44(95%CI: 0.37-0.51) in moderately differentiated tumors and 0.55(95%CI: 0.37-0.51) in poorly differentiated tumors; 0.48(95%CI: 0.36-0.60) in clinical grade (III-IV) NSCLC and 0.75 (95%CI: 0.69-0.81) in clinical grade (I-II) NSCLC; 0.58(95%CI: 0.45-0.71) in T Stage (T1/T2) NSCLC; 0.68(95%CI: 0.49-0.82) in NSCLC patients with lymph node positivity and 0.51(95%CI: 0.43-0.58) in NSCLC patients with lymph node negativity. Conclusions: These results indicated that MTA1 might be a valuable biomarker in the diagnosis of NSCLC. MTA1 overexpression was significantly associated with age ≥60 years, gender, histopathological type, clinical grade (I-II), T stage (T1/T2) and lymph node positivity in NSCLC patients.

Lack of efficacy of pomegranate supplementation for glucose management, insulin levels and sensitivity: evidence from a systematic review and meta-analysis.

BACKGROUND: The potential glucose-lowering effects of pomegranate have been reported in animal and observational studies, but intervention studies in humans have generated mixed results. In this paper, we aimed to conduct a systematic review and meta-analysis of randomized controlled trials (RCTs) to evaluate the precise effects of pomegranate supplementation on measures of glucose control, insulin levels and insulin sensitivity in humans. METHODS: Comprehensive electronic searches were conducted in PubMed, Embase, and the Cochrane Library. Studies included were RCTs that evaluated the changes in diabetes biomarkers among adults (≥18 years) following pomegranate interventions. The predefined outcomes included fasting blood glucose (FBG), fasting blood insulin (FBI), glycated haemoglobin (HbA1c), and homeostatic model assessment of insulin resistance (HOMA-IR). Endpoints were calculated as weighted mean differences (WMDs) with 95% confidence intervals (CIs) by using a random-effects model. Publication bias, subgroup analyses, sensitivity analysis and random-effects meta-regression were also performed to explore the influence of covariates on the net changes in fasting glucose and insulin concentrations. RESULTS: Sixteen eligible trials with 538 subjects were included. The pooled estimates suggested that pomegranate did not significantly affect the measures of FBG (WMD, -0.6 mg/dL; 95% CI, -2.79 to 1.58; P=0.59), FBI (WMD, 0.29 µIU/mL; 95% CI, -1.16 to 1.75; P=0.70), HOMA-IR (WMD, -0.04; 95% CI, -0.53 to 0.46; P=0.88) or HbA1c (WMD, -0.11%; 95% CI, -0.39 to -0.18; P=0.46). Overall, significant heterogeneity was detected for FBI and HOMA-IR, but subgroup analysis could not identify factors significantly influencing these parameters. These results were robust in sensitivity analysis, and no significant publication bias was found in the current meta-analysis. CONCLUSION: Pomegranate intake did not show a notably favourable effect on improvements in glucose and insulin metabolism. The current evidence suggests that daily pomegranate supplementation is not recommended as a potential therapeutic strategy in glycemic management. Further large-scale RCTs with longer duration are required to confirm these results.

Human rotavirus strain Wa downregulates NHE1 and NHE6 expressions in rotavirus-infected Caco-2 cells.

Rotavirus (RV) is the most common cause of severe gastroenteritis and fatal dehydration in human infants and neonates of different species. However, the pathogenesis of rotavirus-induced diarrhea is poorly understood. Secretory diarrhea caused by rotavirus may lead to a combination of excessive secretion of fluid and electrolytes into the intestinal lumen. Fluid absorption in the small intestine is driven by Na+-coupled transport mechanisms at the luminal membrane, including Na+/H+ exchanger (NHE). Here, we performed qRT-PCR to detect the transcription of NHEs. Western blotting was employed for protein detection. Furthermore, immunocytochemistry was used to validate the NHE's protein expression. Finally, intracellular Ca2+ concentration was detected by confocal laser scanning microscopy. The results demonstrated that the NHE6 mRNA and protein expressed in the human colon adenocarcinoma cell line (Caco-2). Furthermore, RV-Wa induced decreased expression of the NHE1 and NHE6 in Caco-2 cell in a time-dependent manner. In addition, intracellular Ca2+ concentration in RV-Wa-infected Caco-2 cells was higher than that in the mock-infected cells. Furthermore, RV-Wa also can downregulate the expression of calmodulin (CaM) and calmodulin kinase II (CaMKII) in Caco-2 cells. These findings provides important insights into the mechanisms of rotavirus-induced diarrhea. Further studies on the underlying pathophysiological mechanisms that downregulate NHEs in RV-induced diarrhea are required.

Two isoreticular metal-organic frameworks with CdSO4-like topology: selective gas sorption and drug delivery.

Two isoreticular metal-organic frameworks with chemical formulae [Cu(L)(4,4'-bipy)(H2O)]n 1.5nCH3CN (1) and [Cu(L)(4,4'-bipy)(H2O)]n·4nH2O (2) (H2L = diphenylmethane-4,4'-dicarboxylic acid) were synthesized and structurally characterized. They show the CdSO4 (6(5) 8) net and have an obvious 1D channel that is spread along the crystallographic c axis. More importantly, 1 shows high selectivity for H2 over N2 and CO2 at low pressure, which could be confirmed via computational calculations using the Connolly algorithm to reveal the size and shape of accessible voids. The incorporation of the drug 5-fluorouracil (5-FU) into the desolvated 1 was around 27.5 wt% per gram of the dehydrated 1. 5-FU is released in a highly controlled and progressive fashion with 61% of the drug released after 95 hours. In addition, we have applied molecular docking calculations to investigate the preferred conformation of 5-FU molecules upon binding to MOF 1. These calculations provide a structural basis to explain the 5-FU release from MOF 1.